Abstract
BackgroundWhile a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. This study combined genetic designs with longitudinal data to achieve a better understanding of this paradox.MethodsWe used longitudinal data from 22,156 individuals in the Swedish Twin Registry (STR) and 25,698 from the Health and Retirement Study (HRS). The STR sample had information about BMI from early adulthood through late-life, and the HRS sample from age 50 through late-life. Survival analysis was applied to investigate age-specific associations between BMI and dementia risk. To examine if the associations are influenced by genetic susceptibility to higher BMI, an interaction between BMI and a polygenic score for BMI (PGSBMI) was included in the models and results stratified into those with genetic predisposition to low, medium, and higher BMI. In the STR, co-twin control models were applied to adjust for familial factors beyond those captured by the PGSBMI.ResultsAt age 35–49, 5 units higher BMI was associated with 15% (95% CI 7–24%) higher risk of dementia in the STR. There was a significant interaction (p = 0.04) between BMI and the PGSBMI, and the association present only among those with genetic predisposition to low BMI (HR 1.38, 95% CI 1.08–1.78). Co-twin control analyses indicated genetic influences. After age 80, 5 units higher BMI was associated with 10–11% lower risk of dementia in both samples. There was a significant interaction between late-life BMI and the PGSBMI in the STR (p = 0.01), but not the HRS, with the inverse association present only among those with a high PGSBMI (HR 0.70, 95% CI 0.52–0.94). No genetic influences were evident from co-twin control models of late-life BMI.ConclusionsNot only does the association between BMI and dementia differ depending on age at BMI measurement, but also the effect of genetic influences. In STR, the associations were only present among those with a BMI in opposite direction of their genetic predisposition, indicating that the association between BMI and dementia across the life course might be driven by environmental factors and hence likely modifiable.
Highlights
While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk
While a high BMI in midlife has been associated with increased risk of dementia in most studies, a high BMI in late-life may be associated with a decreased risk of dementia—this is known as the “obesity paradox” [3]
Using longitudinal data from two large cohorts, the Swedish Twin Registry (STR) and Health and Retirement Study (HRS), we could confirm the age-specific effects of BMI on the risk of dementia, with higher BMI in adulthood and midlife being associated with higher risk of dementia in the STR, while a higher BMI in late-life was associated with a lower risk in both samples
Summary
While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. As a high body mass index (BMI) is associated with many age-related diseases, this increase in obesity prevalence, together with the demographic shift in the proportion of older individuals, calls for substantial efforts to better understand how BMI affects longterm health outcomes. A GWAS identified several genetic variants with age-specific effects on BMI, most of which are more important for BMI prior to age 55 than at later ages [7] In line with these latter findings, Song et al showed that while a genetic score comprised of 97 genetic variants for BMI was associated with BMI across all age categories, the effect declined in late-life [8]. The negative health effects associated with higher BMI differ by age at BMI measurement, and the genetic influences and the underlying biological mechanisms
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